Murine minor histocompatibility (H) antigens are derived from natural proteins that happen to be antigenic among different strains of mice because they are polymorphic. They are significant barriers to allogeneic tissue transplantation and constitute a realistic model system for understanding how the immune system deals with natural proteins, expressed at physiological levels, in normal and pathological states. The objective of the proposed research is to elucidate the basic cellular mechanisms that determine immune responses to minor H antigens in vivo. The products of certain minor H genes selectively stimulate CD8+ T cells, whereas products of others stimulate CD4 T cells. This differential stimulation is a critical element of the immune response because mature CD8+ cells function as cytotoxic T (Tc) cells and mature CD4+ cells function primarily as helper T (Th) cells. Our first objective is to determine why products of minor H genes stimulate different T cell subsets. We will determine whether the major avenue leading to presentation of minor H antigens that stimulate Th cells is the transfer of minor H proteins in vivo from MHC class II-negative cells to antigen presenting cells. These studies will clarify athe dynamics of how self-antigens come to be presented to the immune system in vivo. We will also determine whether products of minor H genes stimulate deferent T cell subsets because immunogenic peptides derived from them are presented by only a restricted number of MHC allotypes. Our second objective is to determine the avenues by which Signal 2 (i.e., help) can be delivered in Tc responses to minor H antigens in vivo. We will examine the role of different cell types in the delivery of Signal 2. We will also examine whether various autoimmune disorders and environmentally-acquired microorganisms deliver Signal 2 to c cell responses against minor H antigens in vivo. These studies will clarify the types of stimuli that can determine Tc immunity and are also likely to open new experimental directions into how apparently unrelated immune responses can affect one another.